Converting Nanotoxicity Data to Information Using Artificial Intelligence and Simulation.

Decades of nanotoxicology research have generated extensive and diverse data sets. However, data is not equal to information. The question is how to extract critical information buried in vast data streams. Here we show that artificial intelligence (AI) and molecular simulation play key roles in transforming nanotoxicity data into critical information, i.e., constructing the quantitative nanostructure (physicochemical properties)-toxicity relationships, and elucidating the toxicity-related molecular mechanisms. For AI and molecular simulation to realize their full impacts in this mission, several obstacles must be overcome. These include the paucity of high-quality nanomaterials (NMs) and standardized nanotoxicity data, the lack of model-friendly databases, the scarcity of specific and universal nanodescriptors, and the inability to simulate NMs at realistic spatial and temporal scales. This review provides a comprehensive and representative, but not exhaustive, summary of the current capability gaps and tools required to fill these formidable gaps. Specifically, we discuss the applications of AI and molecular simulation, which can address the large-scale data challenge for nanotoxicology research. The need for model-friendly nanotoxicity databases, powerful nanodescriptors, new modeling approaches, molecular mechanism analysis, and design of the next-generation NMs are also critically discussed. Finally, we provide a perspective on future trends and challenges.

Toward Nano-Specific In Silico NAMs: How to Adjust Nano-QSAR to the Recent Advancements of Nanotoxicology?

The rapid development of engineered nanomaterials (ENMs) causes humans to become increasingly exposed to them. Therefore, a better understanding of the health impact of ENMs is highly demanded. Considering the 3Rs (Replacement, Reduction, and Refinement) principle, in vitro and computational methods are excellent alternatives for testing on animals. Among computational methods, nano-quantitative structure-activity relationship (nano-QSAR), which links the physicochemical and structural properties of EMNs with biological activities, is one of the leading method. The nature of toxicological experiments has evolved over the last decades; currently, one experiment can provide thousands of measurements of the organism's functioning at the molecular level. At the same time, the capacity of the in vitro systems to mimic the human organism is also improving significantly. Hence, the authors would like to discuss whether the nano-QSAR approach follows modern toxicological studies and takes full advantage of the opportunities offered by modern toxicological platforms. Challenges and possibilities for improving data integration are underlined narratively, including the need for a consensus built between the in vitro and the QSAR domains.

In the View of Electrons Transfer and Energy Conversion: The Antimicrobial Activity and Cytotoxicity of Metal-Based Nanomaterials and Their Applications.

The global pandemic and excessive use of antibiotics have raised concerns about environmental health, and efforts are being made to develop alternative bactericidal agents for disinfection. Metal-based nanomaterials and their derivatives have emerged as promising candidates for antibacterial agents due to their broad-spectrum antibacterial activity, environmental friendliness, and excellent biocompatibility. However, the reported antibacterial mechanisms of these materials are complex and lack a comprehensive understanding from a coherent perspective. To address this issue, a new perspective is proposed in this review to demonstrate the toxic mechanisms and antibacterial activities of metal-based nanomaterials in terms of energy conversion and electron transfer. First, the antimicrobial mechanisms of different metal-based nanomaterials are discussed, and advanced research progresses are summarized. Then, the biological intelligence applications of these materials, such as biomedical implants, stimuli-responsive electronic devices, and biological monitoring, are concluded based on trappable electrical signals from electron transfer. Finally, current improvement strategies, future challenges, and possible resolutions are outlined to provide new insights into understanding the antimicrobial behaviors of metal-based materials and offer valuable inspiration and instructional suggestions for building future intelligent environmental health.

Adapting the in vitro micronucleus assay (OECD Test Guideline No. 487) for testing of manufactured nanomaterials: recommendations for best practices.

The current Organisation for Economic Co-Operation and Development test guideline number 487 (OECD TG No. 487) provides instruction on how to conduct the in vitro micronucleus assay. This assay is one of the gold standard approaches for measuring the mutagenicity of test items; however, it is directed at testing low molecular weight molecules and may not be appropriate for particulate materials (e.g. engineered nanoparticles [ENPs]). This study aimed to adapt the in vitro micronucleus assay for ENP testing and underpins the development of an OECD guidance document. A harmonized, nano-specific protocol was generated and evaluated by two independent laboratories. Cell lines utilized were human lymphoblastoid (TK6) cells, human liver hepatocytes (HepG2) cells, Chinese hamster lung fibroblast (V79) cells, whole blood, and buffy coat cells from healthy human volunteers. These cells were exposed to reference ENPs from the Joint Research Council (JRC): SiO2 (RLS-0102), Au5nm and Au30nm (RLS-03, RLS-010), CeO2 (NM212), and BaSO4 (NM220). Tungsten carbide-cobalt (WC/Co) was used as a trial particulate positive control. The chemical controls were positive in all cell cultures, but WC/Co was only positive in TK6 and buffy coat cells. In TK6 cells, mutagenicity was observed for SiO2- and both Au types. In HepG2 cells, Au5nm and SiO2 showed sub-two-fold increases in micronuclei. In V79 cells, whole blood, and buffy coat cells, no genotoxicity was detected with the test materials. The data confirmed that ENPs could be tested with the harmonized protocol, additionally, concordant data were observed across the two laboratories with V79 cells. WC/Co may be a suitable particulate positive control in the in vitro micronucleus assay when using TK6 and buffy coat cells. Detailed recommendations are therefore provided to adapt OECD TG No. 487 for testing ENP.

Potential Biosafety of Mxenes: Stability, Biodegradability, Toxicity and Biocompatibility.

MXenes are two-dimensional nanomaterials with unique properties that are widely used in various fields of research, mostly in the field of energy. Fewer publications are devoted to MXene application in biomedicine and the question is: are MXenes safe for use in biological systems? The sharp edges of MXenes provide the structure of "nanoknives" which cause damage in direct physical contact with cells. This is effectively used for antibacterial research. However, on the other hand, most studies in cultured cells and rodents report that they do not cause obvious signs of cytotoxicity and are fully biocompatible. The aim of our review was to consider whether MXenes can really be considered non-toxic and biocompatible. Often the last two concepts are confused. We first reviewed aspects such as the stability and biodegradation of MXenes, and then analyzed the mechanisms of toxicity and their consequences for bacteria, cultured cells, and rodents, with subsequent conclusions regarding their biocompatibility.

Nanotoxicity of two-dimensional nanomaterials on human skin and the structural evolution of keratin protein.

Two-dimensional (2D) materials have been increasingly widely used in biomedical and cosmetical products nowadays, yet their safe usage in human body and environment necessitates a comprehensive understanding of their nanotoxicity. In this work, the effect of pristine graphene and graphene oxide (GO) on the adsorption and conformational changes of skin keratin using molecular dynamics simulations. It is found that skin keratin can be absorbed through various noncovalent driving forces, such as van der Waals (vdW) and electrostatics. In the case of GO, the oxygen-containing groups prevent tighter contact between skin keratin and the graphene basal plane through steric effects and electrostatic repulsion. On the other hand, electrostatic attraction and hydrogen bonding enhance their binding affinity to positively charged residues such as lysine and arginine. The secondary structure of skin keratin is better preserved in GO system, suggesting that GO has good biocompatibility. The charged groups on GO surface perform as the hydrogen bond acceptors, which is like to the natural receptors of keratin in this physiological environment. This work contributes to a better knowledge of the nanotoxicity of cutting-edge 2D materials on human health, thereby advancing their potential biological applications.

Environmental behaviors and toxic mechanisms of engineered nanomaterials in soil.

Engineered nanomaterials (ENMs) are inevitably released into the environment with the exponential application of nanotechnology. Parts of ENMs eventually accumulate in the soil environment leading to potential adverse effects on soil ecology, crop production, and human health. Therefore, the safety application of ENMs on soil has been widely discussed in recent years. More detailed safety information and potential soil environmental risks are urgently needed. However, most of the studies on the environmental effects of metal-based ENMs have been limited to single-species experiments, ecosystem processes, or abiotic processes. The present review formulated the source and the behaviors of the ENMs in soil, and the potential effects of single and co-exposure ENMs on soil microorganisms, soil fauna, and plants were introduced. The toxicity mechanism of ENMs to soil organisms was also reviewed including oxidative stress, the release of toxic metal ions, and physical contact. Soil properties affect the transport, transformation, and toxicity of ENMs. Toxic mechanisms of ENMs include oxidative stress, ion release, and physical contact. Joint toxic effects occur through adsorption, photodegradation, and loading. Besides, future research should focus on the toxic effects of ENMs at the food chain levels, the effects of ENMs on plant whole-lifecycle, and the co-exposure and long-term toxicity effects. A fast and accurate toxicity evaluation system and model method are urgently needed to solve the current difficulties. It is of great significance for the sustainable development of ENMs to provide the theoretical basis for the ecological risk assessment and environmental management of ENMs.

Worse pulmonary function in association with cumulative exposure to nanomaterials. Hints of a mediation effect via pulmonary inflammation.

BACKGROUND: Today, nanomaterials are broadly used in a wide range of industrial applications. Such large utilization and the limited knowledge on to the possible health effects have raised concerns about potential consequences on human health and safety, beyond the environmental burden. Given that inhalation is the main exposure route, workers exposed to nanomaterials might be at risk of occurrence of respiratory morbidity and/or reduced pulmonary function. However, epidemiological evidence regarding the association between cumulative exposure to nanomaterials and respiratory health is still scarce. This study focused on the association between cumulative exposure to nanomaterials and pulmonary function among 136 workers enrolled in the framework of the European multicentric NanoExplore project. RESULTS: Our findings suggest that, independently of lifelong tobacco smoking, ethnicity, age, sex, body mass index and physical activity habits, 10-year cumulative exposure to nanomaterials is associated to worse FEV1 and FEF25 - 75%, which might be consistent with the involvement of both large and small airway components and early signs of airflow obstruction. We further explored the hypothesis of a mediating effect via airway inflammation, assessed by interleukin (IL-)10, IL-1ß and Tumor Necrosis Factor alpha (TNF-α), all quantified in the Exhaled Breath Condensate of workers. The mediation analysis results suggest that IL-10, TNF-α and their ratio (i.e., anti-pro inflammatory ratio) may fully mediate the negative association between cumulative exposure to nanomaterials and the FEV1/FVC ratio. This pattern was not observed for other pulmonary function parameters. CONCLUSIONS: Safeguarding the respiratory health of workers exposed to nanomaterials should be of primary importance. The observed association between cumulative exposure to nanomaterials and worse pulmonary function parameters underscores the importance of implementing adequate protective measures in the nanocomposite sector. The mitigation of harmful exposures may ensure that workers can continue to contribute productively to their workplaces while preserving their respiratory health over time.

Biological mechanism of ZnO nanomaterials.

Modern nanotechnology has made zinc oxide nanomaterials (ZnO NMts) multifunctional, stable, and low cost, enabling them to be widely used in commercial and biomedical fields. With its wide application, the risk of human direct contact and their release into the environment also increases. This review aims to summarize the toxicity studies of ZnO NMts in vivo, including neurotoxicity, inhalation toxicity, and reproductive toxicity. The antibacterial and antiviral mechanisms of ZnO NMts in vitro and the toxicity to eukaryotic cells were summarized. The summary found that it was mainly related to reactive oxygen species (ROS) produced by oxidative stress. It also discusses the potential harm to body and the favorable prospects of the widespread use of antibacterial and antiviral in the future medical field. The review also emphasizes that the dosage and use method of ZnO NMts will be the focus of future biomedical research.

Recent Trends in Chemical Sensors for Detecting Toxic Materials.

Industrial development has led to the widespread production of toxic materials, including carcinogenic, mutagenic, and toxic chemicals. Even with strict management and control measures, such materials still pose threats to human health. Therefore, convenient chemical sensors are required for toxic chemical monitoring, such as optical, electrochemical, nanomaterial-based, and biological-system-based sensors. Many existing and new chemical sensors have been developed, as well as new methods based on novel technologies for detecting toxic materials. The emergence of material sciences and advanced technologies for fabrication and signal-transducing processes has led to substantial improvements in the sensing elements for target recognition and signal-transducing elements for reporting interactions between targets and sensing elements. Many excellent reviews have effectively summarized the general principles and applications of different types of chemical sensors. Therefore, this review focuses on chemical sensor advancements in terms of the sensing and signal-transducing elements, as well as more recent achievements in chemical sensors for toxic material detection. We also discuss recent trends in biosensors for the detection of toxic materials.

Zebrafish Insights into Nanomaterial Toxicity: A Focused Exploration on Metallic, Metal Oxide, Semiconductor, and Mixed-Metal Nanoparticles.

Nanomaterials are widely used in various fields, and ongoing research is focused on developing safe and sustainable nanomaterials. Using zebrafish as a model organism for studying the potentially toxic effects of nanomaterials highlights the importance of developing safe and sustainable nanomaterials. Studies conducted on nanomaterials and their toxicity and potential risks to human and environmental health are vital in biomedical sciences. In the present review, we discuss the potential toxicity of nanomaterials (inorganic and organic) and exposure risks based on size, shape, and concentration. The review further explores various types of nanomaterials and their impacts on zebrafish at different levels, indicating that exposure to nanomaterials can lead to developmental defects, changes in gene expressions, and various toxicities. The review also covers the importance of considering natural organic matter and chorion membranes in standardized nanotoxicity testing. While some nanomaterials are biologically compatible, metal and semiconductor nanomaterials that enter the water environment can increase toxicity to aquatic creatures and can potentially accumulate in the human body. Further investigations are necessary to assess the safety of nanomaterials and their impacts on the environment and human health.

Recent advances on environmental behavior of Cu-based nanomaterials in soil-plant system: A review.

In recent years, copper-based nanomaterials (Cu-based NMs) have shown great potential in promoting agriculture development due to their special physicochemical characteristics. With the mass production and overuse of Cu-based NMs, there are potential effects on the soil-plant environment. Soil organisms, especially soil microorganisms, play a significant part in terrestrial or soil ecosystems; plants, as indirect organisms with soil-related Cu-based NMs, may affect human health through plant agricultural products. Understanding the accumulation and transformation of Cu-based NMs in soil-plant systems, as well as their ecotoxicological effects and potential mechanisms, is a prerequisite for the scientific assessment of environmental risks and safe application. Therefore, based on the current literature, this review: (i) introduces the accumulation and transformation behaviors of Cu-based NMs in soil and plant systems; (ii) focuses on the ecotoxicological effects of Cu-based NMs on a variety of organisms (microorganisms, invertebrates, and plants); (iii) reveals their corresponding toxicity mechanisms. It appears from studies hitherto made that both Cu-based NMs and released Cu2+ may be the main reasons for toxicity. When Cu-based NMs enter the soil-plant environment, their intrinsic physicochemical properties, along with various environmental factors, could also affect their transport, transformation, and biotoxicity. Therefore, we should push for intensifying the multi-approach research that focuses on the behaviors of Cu-based NMs in terrestrial exposure environments, and mitigates their toxicity to ensure the promotion of Cu-based NMs.

Quantitative Prediction of Inorganic Nanomaterial Cellular Toxicity via Machine Learning.

Organic chemistry has seen colossal progress due to machine learning (ML). However, the translation of artificial intelligence (AI) into materials science is challenging, where biological behavior prediction becomes even more complicated. Nanotoxicity is a critical parameter that describes their interaction with the living organisms screened in every bio-related research. To prevent excessive experiments, such properties have to be pre-evaluated. Several existing ML models partially fulfill the gap by predicting whether a nanomaterial is toxic or not. Yet, this binary categorization neglects the concentration dependencies crucial for experimental scientists. Here, an ML-based approach is proposed to the quantitative prediction of inorganic nanomaterial cytotoxicity achieving the precision expressed by 10-fold cross-validation (CV) Q2  = 0.86 with the root mean squared error (RMSE) of 12.2% obtained by the correlation-based feature selection and grid search-based model hyperparameters optimization. To provide further model flexibility, quantitative atom property-based nanomaterial descriptors are introduced allowing the model to extrapolate on unseen samples. Feature importance is calculated to find an interpretable model with optimal decision-making. These findings allow experimental scientists to perform primary in silico candidate screening and minimize the number of excessive, labor-intensive experiments enabling the rapid development of nanomaterials for medicinal purposes.

Current status and future challenges of genotoxicity OECD Test Guidelines for nanomaterials: a workshop report.

Genotoxicity testing for nanomaterials remains challenging as standard testing approaches require some adaptation, and further development of nano-specific OECD Test Guidelines (TGs) and Guidance Documents (GDs) are needed. However, the field of genotoxicology continues to progress and new approach methodologies (NAMs) are being developed that could provide relevant information on the range of mechanisms of genotoxic action that may be imparted by nanomaterials. There is a recognition of the need for implementation of new and/or adapted OECD TGs, new OECD GDs, and utilization of NAMs within a genotoxicity testing framework for nanomaterials. As such, the requirements to apply new experimental approaches and data for genotoxicity assessment of nanomaterials in a regulatory context is neither clear, nor used in practice. Thus, an international workshop with representatives from regulatory agencies, industry, government, and academic scientists was convened to discuss these issues. The expert discussion highlighted the current deficiencies that exist in standard testing approaches within exposure regimes, insufficient physicochemical characterization, lack of demonstration of cell or tissue uptake and internalization, and limitations in the coverage of genotoxic modes of action. Regarding the latter aspect, a consensus was reached on the importance of using NAMs to support the genotoxicity assessment of nanomaterials. Also highlighted was the need for close engagement between scientists and regulators to (i) provide clarity on the regulatory needs, (ii) improve the acceptance and use of NAM-generated data, and (iii) define how NAMs may be used as part of weight of evidence approaches for use in regulatory risk assessments.

Immunotoxicity of engineered nanomaterials and their role in asthma.

The toxicity of engineered nanomaterials (ENMs) in vivo and in vitro has formed the basis of most studies. However, the toxicity of ENMs, particularly on the immune system, i.e. immunotoxicity, and their role in manipulating it, are less known. This review addresses the initiation or exacerbation as well as the attenuation of allergic asthma by a variety of ENMs and how they may be used in drug delivery to enhance the treatment of asthma. This review also highlights a few research gaps in the study of the immunotoxicity of ENMs, for example, the potential drawbacks of assays used in immunotoxicity assays; the potential role of hormesis during dosing of ENMs; and the variables that result in discrepancies among different studies, such as the physicochemical properties of ENMs, differences in asthmatic animal models, and different routes of administration.

Recent progress on the heavy metals ameliorating potential of engineered nanomaterials in rice paddy: a comprehensive outlook on global food safety with nanotoxicitiy issues.

Soil contamination with toxic heavy metals (HMs) poses a serious threat to global food safety, soil ecosystem and human health. The rapid industrialization, urbanization and extensive application of agrochemicals on arable land have led to paddy soil pollution worldwide. Rice plants easily accumulate toxic HMs from contaminated agricultural soils, which ultimately accumulated in grains and enters the food chain. Although, physical and chemical remediation techniques have been used for the treatment of HMs-contaminated soils, however, they also have many drawbacks, such as toxicity, capital investment and environmental-associated hazards. Recently, engineered nanomaterials (ENMs) have gained substantial attention owing to their promising environmental remediation applications. Numerous studies have revealed the use of ENMs for reclamation of toxic HMs from contaminated environment. This review mainly focuses on HMs toxicity in paddy soils along with potential health risks to humans. It also provides a critical outlook on the recent advances and future perspectives of nanoremediation strategies. Additionally, we will also propose the interacting mechanism of HMs-ENMs to counteract metal-associated phytotoxicities in rice plants to achieve global food security and environmental safety.

Biochemical effects of copper nanomaterials in human hepatocellular carcinoma (HepG2) cells.

In dose-response and structure-activity studies, human hepatic HepG2 cells were exposed for 3 days to nano Cu, nano CuO or CuCl2 (ions) at doses between 0.1 and 30 ug/ml (approximately the no observable adverse effect level to a high degree of cytotoxicity). Various biochemical parameters were then evaluated to study cytotoxicity, cell growth, hepatic function, and oxidative stress. With nano Cu and nano CuO, few indications of cytotoxicity were observed between 0.1 and 3 ug/ml. In respect to dose, lactate dehydrogenase and aspartate transaminase were the most sensitive cytotoxicity parameters. The next most responsive parameters were alanine aminotransferase, glutathione reductase, glucose 6-phosphate dehydrogenase, and protein concentration. The medium responsive parameters were superoxide dismutase, gamma glutamyltranspeptidase, total bilirubin, and microalbumin. The parameters glutathione peroxidase, glutathione reductase, and protein were all altered by nano Cu and nano CuO but not by CuCl2 exposures. Our chief observations were (1) significant decreases in glucose 6-phosphate dehydrogenase and glutathione reductase was observed at doses below the doses that show high cytotoxicity, (2) even high cytotoxicity did not induce large changes in some study parameters (e.g., alkaline phosphatase, catalase, microalbumin, total bilirubin, thioredoxin reductase, and triglycerides), (3) even though many significant biochemical effects happen only at doses showing varying degrees of cytotoxicity, it was not clear that cytotoxicity alone caused all of the observed significant biochemical effects, and (4) the decreased glucose 6-phosphate dehydrogenase and glutathione reductase support the view that oxidative stress is a main toxicity pathway of CuCl2 and Cu-containing nanomaterials.

Nanomaterial-induced toxicity in pathophysiological models representative of individuals with pre-existing medical conditions.

The integration of nanomaterials (NMs) into an ever-expanding number of daily used products has proven to be highly desirable in numerous industries and applications. Unfortunately, the same "nano" specific physicochemical properties, which make these materials attractive, may also contribute to hazards for individuals exposed to these materials. In 2021, it was estimated that 7 out of 10 deaths globally were accredited to chronic diseases, such as chronic liver disease, asthma, and cardiovascular-related illnesses. Crucially, it is also understood that a significant proportion of global populace numbering in the billions are currently living with a range of chronic undiagnosed health conditions. Due to the significant number of individuals affected, it is important that people suffering from chronic disease also be considered and incorporated in NM hazard assessment strategies. This review examined and analyzed the literature that focused on NM-induced adverse health effects in models which are representative of individuals exhibiting pre-existing medical conditions with focus on the pulmonary, cardiovascular, hepatic, gastrointestinal, and central nervous systems. The overall objective of this review was to outline available data, highlighting the important role of pre-existing disease in NM-induced toxicity with the aim of establishing a weight of evidence approach to inform the public on the potential hazards posed by NMs in both healthy and compromised persons in general population.

Using Machine Learning to Predict Adverse Effects of Metallic Nanomaterials to Various Aquatic Organisms.

The wide production and use of metallic nanomaterials (MNMs) leads to increased emissions into the aquatic environments and induces high potential risks. Experimentally evaluating the (eco)toxicity of MNMs is time-consuming and expensive due to the multiple environmental factors, the complexity of material properties, and the species diversity. Machine learning (ML) models provide an option to deal with heterogeneous data sets and complex relationships. The present study established an in silico model based on a machine learning properties-environmental conditions-multi species-toxicity prediction model (ML-PEMST) that can be applied to predict the toxicity of different MNMs toward multiple aquatic species. Feature importance and interaction analysis based on the random forest method indicated that exposure duration, illumination, primary size, and hydrodynamic diameter were the main factors affecting the ecotoxicity of MNMs to a variety of aquatic organisms. Illumination was demonstrated to have the most interaction with the other features. Moreover, incorporating additional detailed information on the ecological traits of the test species will allow us to further optimize and improve the predictive performance of the model. This study provides a new approach for ecotoxicity predictions for organisms in the aquatic environment and will help us to further explore exposure pathways and the risk assessment of MNMs.

Recent Advances in the Biological Responses to Nano-black Phosphorus: Understanding the Importance of Intrinsic Properties and Cell Types.

The production scalability and increasing demand for nano-black phosphorus materials (nano-BPs) inevitably lead to their environmental leakage, thereby raising the risk of human exposure through inhalation, ingestion, dermal, and even intravenous pathways. Consequently, a systematic evaluation of their potential impacts on human health is necessary. This Review outlines recent progress in the understanding of various biological responses to nano-BPs. Attention is particularly given to the inconsistent toxicological findings caused by a wide variation of nano-BPs' physicochemical properties, toxicological testing methods, and cell types examined in each study. Additionally, cellular uptake and intracellular trafficking, cell death modes, immunological effects, and other biologically relevant processes are discussed in detail, providing evidence for the potential health implications of nano-BPs. Finally, we address the remaining challenges related to the health risk evaluation of nano-BPs and propose a broader range of applications for these promising nanomaterials.